Millions of women in the US suffer from endometriosis, a poorly understood disease characterized by the presence of lesions composed of endometrial glands and stroma located outside the uterus. For women with deeply invasive endometriosis that does not respond to hormonal therapy, surgical removal can be as extensive as cancer surgery, requiring segmental bowel excision and extirpative resection of pelvic tissues. Progesterone-based therapy has become the mainstay in treating endometriosis, but progesterone-resistance occurs in 40% of patients. Currently, the molecular mechanisms underlying the disease phenotypes remain unclear and diagnostic and predictive markers are urgently needed. There is a growing body of evidence that genetic contributions play a pivotal role in the development of endometriosis and may explain the different types and severity of endometriosis. Importantly, our preliminary studies of endometriotic lesions showed that 26% of lesions harbored somatic, cancer-associated mutations (acquired mutations in rogue cells) in genes known as ?drivers? of cancer. Notably, the lesions containing the ?driver? mutations were associated with deeply invasive endometriosis, a particularly painful and disabling form of endometriosis. These exciting results suggest a new research direction to understand the pathogenesis of endometriosis; specifically, a biologically informed, molecular disease classification to improve diagnosis and management. What is now needed is a comprehensive catalogue of somatic variants of endometriosis lesions and correlation of molecular alterations with disease phenotypes. Based on these results, we propose to establish a molecular classification of endometriosis correlated with the clinical phenotype of disease. This study includes key investigators with unique and complementary expertise including reproductive biology, molecular genetics and genomics, pathology, and bioinformatics. First, we will use laser capture microdissection to study 300 existing endometriosis specimens for changes in these cancer-associated genes. Then, we will validate the findings in a prospective study of 100 women with endometriosis, and 35 control subjects. Finally, we will rigorously test how these cancer- driver mutations promote lesion development in endometriosis using three experimental models used in endometriosis research. The expected results will enhance our understanding of the pathophysiology of endometriosis and the mechanism of progesterone-resistance. The studies will establish a biologically informed molecular classification of endometriosis and represent the first step toward personalized medical treatment of endometriosis.